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Genetic aspects of craniofacial disorders

Genetic aspects of craniofacial disorders. Craniofacial disorders. may be accompanied by considerable discomfort and stress on the side of the patient , because it may be associated with a noticeable cosmetic problem , which is individually perceived

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Genetic aspects of craniofacial disorders

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  1. Geneticaspectsofcraniofacialdisorders

  2. Craniofacialdisorders • maybeaccompanied by considerablediscomfortand stress on thesideofthepatient,becauseitmaybeassociatedwith a noticeablecosmeticproblem,whichisindividuallyperceived • The role ofgeneticcounselingisnecessary in thediagnosticprocesswithrespect to possiblerecurrence

  3. Disorders of teeth, jaws and periodontium

  4. Teeth • Numerousdefectsoftheteeth • Hypodontia/oligodontia • Hyperodontia

  5. Hypodontia • is the condition at which the patient has missing teeth as a result of their failure to develop. • Most common anomaly of human dentition in a population • Hypodontia: 1-6 missing teeth • Oligodontia: more then 6 missing teeth • anodontia : missing all teeth- rare

  6. Hypodontia- prevalence • In caucasians, the most common missing teeth are the wisdom teeth (25-35%), the upper lateral incisors (20%) ,the lower ortheuppersecond premolars (30%), with a 4:1 female to male ratio. • The prevalence of missing primary teeth is found at 0,1-0,9%, with a 1:1 male to female ratio. Excluding the third molars, missing permanent dentition accounts for 3-6%. • 30-50% of people with missing primary teeth will have missing permanent teeth, as well.

  7. Hypodontia-etiology • Among the possible causes are genetic, hormonal, environmental and infectiousfactorsduringdentaldevelopment. • missing teeth have been reported in association with increased maternal age, low birth weight, infection during embryonic life • Hypodontia can be associated with genetic disorders such as ectodermal dysplasia or Down syndromeand can also been seen in people with cleft lip and palate. • Etiology due to hormonal defects: idiopathic hypoparathyroidism and pseudohypoparathyroidism. • Environmental causes involving exposure to PCBs (ex.dioxin), radiation,anticancer chemotherapeutic agents, allergy and toxic epidermal necrolysis after drugs.

  8. Geneticcausesofhypodontia • isolated Severalgenes are known in assotiation PAX9(14q12),MSX1(4p16), WNT10A(2q35), AXIN2(17q24.1) (ovarian and CRC cancer susceptibility) Inheritance: autosomal dominant orrecesive(rare) IRF6(1q32.3),TGFA(2p13),FGFR1(8p11.23), EDA(Xq13.1),EDARADD(1q42),LTBP3(11q13.1), • syndromic Ectodermaldysplasia Orofaciodigital syndrome,etc.

  9. Ectodermaldysplasia • there are abnormalities of two or more ectodermal structures such as the hair, teeth, nails, sweat glands, cranial-facial structure, digits and other parts of the body. • more than 150 different syndromes have been identified • Ectodermaldysplasia,anhidrotic hypotrichosis, fine-brittle-scantyhair, absentorscantyeyelashes,eyebrows, hypodontia /anodontia, hypoplasticorabsentmucousglands dangerofoverheating • Genetic heterogenity XR, AR,AD • Heterozygous females show variable expressivity (mild manifestations) including hypodontia, conical teeth, reduction in scalp/body hair Genes: EDA, EDAR, EDARADD

  10. Hyperodontia • Hyperdontia is the condition of having supernumerary teeth, or teeth which appear in addition to the regular number of teeth. Supernumerary teeth can be classified by shape and by position. • The atypicalshapes include:supplemental tuberculate, conical, compoundodontoma (multiple small tooth-like forms),complexodontoma (a disorganized mass of dental tissue) • By position a supernumerary tooth may be referred to as a mesiodens, a paramolar, or a distomolar. The most common supernumerary tooth is a mesiodens, which is a mal-formed, peg-like tooth that occurs between the maxillary central incisors. Fourth and fifth molars that form behind the third molars are another kind of supernumerary teeth.

  11. Hyperodontia-causes • there is evidence of hereditary factors along with some evidence of environmental factors leading to this condition-multifactorialinheritance • Many supernumerary teeth never erupt, but they may delay eruption of nearby teeth or cause other dental or orthodontic problems. Dental X-rays are often used to diagnose hyperdontia. • Supernumerary teeth in deciduous (baby) teeth are less common than in permanent teeth. • Hyperdontia is seen in a number of geneticdisorders, including CleidocranialdysostosisorGardner´s syndrome

  12. Cleidocranialdysplasia • persistently open skullsutureswithbulgingcalvaria, hypoplasiaoraplasiaoftheclaviclespermittingabnormalfacility in opposingtheshoulders, widepubicsymphysis, shortmiddlephalanxofthefifthfingers, dentalanomalies, andoftenvertebralmalformation • Occurence 1:100 000 • Inheritence AD,variableexpressivity • Location 6p21, gene CBFA1(RUNX2) • One third of patients represent new mutations

  13. Cleidocranialdysplasia-unfavorableeffects • 18% scoliosis • 28% coxavara, coxavalga • 57% pedesplani • 34% inflammationoftheparanasalsinusesfrequently • 70% oral disorders • 19% difficultybreathing • 39% deafness

  14. Cleidocranialdysplasia- oral symptoms • Cleft palate(submucous )Narrow, high-arched palate • Delayed eruption of deciduous teethDelayed eruption of permanent teethSupernumerary teethRetention cystsEnamel hypoplasia • Delayedclosuremandibularsymphysis, prognathiarelative-normalmandibulargrowthand limited growthofpraemaxila

  15. Teeth- disordersofenamel • amelogenesisimperfecta -presents with abnormal formation of the enamel or external layer of teeth. inheritance: AD, AR, X-linked • Syndromicassociation (trichodentoosseous syndrome – TDO-AD, Kohlschutter syndrome –AR -epilepsy,mentalretardation,amelogenesisimp.) • Non-geneticformsabnormalenamel (fluorosis, the use oftetracyclineantibiotics,etc)

  16. Teeth- dentin disorders • Dentinogenesisimperfecta • Non-syndromic AD inheritence • syndromicassotiation-diffrentformsofosteogenesisimperfecta- brittle bone disease, defectiveconnectivetissues(AD,AR, defectsofcollagen I)- COL1A1,COL1A2 genes • Disordersof dentin in number of systemic diseases associated with impaired metabolism of calcium and phosphate (eg. Hypophosphatemicrickets ,hypoparathyroidismetc)

  17. Teeth • Caries- multifactorial, interaction between environmental and genetic factors - susceptibility oftoothtissue, compositionof oral microflora, eatinghabits, oral hygiene

  18. Periodontaldiseases • Frequent cause oftoothloss • Multifactorial • Syndromicassotiation Papillon-Lefévre syndrome • Inheritenceautosomalrecessive • occurence 1-4/1 000 000 • Keratosispalmoplantaris • periodontopathia

  19. Anomaliesofjaws • Prognathia(excessivegrowthofmaxilla) affectsabout 14% population, multifactorialprobably, withhighcorrelationbetweensiblings. • Progenia(excessivegrowthof mandibula, often in allthreedimensions) affects 3-9% population polygenic (multifaktorial) familialcaseswith AD inherritencehavebeenreported(the best known is the case of the Habsburgs)

  20. Facial cleft defects

  21. Cleft lip andpalate-CLP • CL- incidence : 1/500-1/1000 • CP- incidence: 1/2500

  22. Cleftdefects-clasification • clefts typicallip (cheiloschisis)lip + palate (cheilognathoschisis)palate-isolated(palatoschisis)total (cheilognathopalatoschisis). • clefts atypicalCrossupper middle (nose, upper lip, upper lip defect with defect of praemaxilla)lower middle (lower lip, lower lip + jaw)oblique (lip + face, + faces of the lower lid, with cleft palate typical + atypical).

  23. Facialclefts -pathogenesis • Cleft lip andpalate: failure of fusion of the maxillary and medial nasal processes (formation of the primary palate). • Cleftpalate: failure of fusion of the lateral palatine processes, the nasal septum, and/or the median palatine processes (formationofthesecondarypalate)

  24. Cleft lip andpalate- cause • Multifactorialwithsignificant inheritance component Enviromentalfactors:viruses , toxoplasmosis, CMV,hypervitaminosis A + D, ATB(tetracyclines, erythromycine), AEDs, corticoids, X-ray, drugs, organicsolvents ,otherteratogens • Congenitalchromosomalaberration • SyndromesasociatedwithCL/CP/CLP

  25. Cleft lip andpalate-ethnicdifferences • most common in Caucasians and Japanese • leastfrequently in Negroidrace

  26. Cleft lip andpalate- empiricrisks(Harper)

  27. Empirical risk according to severityofdefect Defect risk forsibs Bilateral CLP 5,7 % Unilateral CLP 4,2 % Unilateral CL 2,5 %

  28. Chromosomalaberrationassociatedwith CLP/CP • trisomy 13 • trisomy 18 • Structuralaberrationsautosomes • velocardiofacial syndrome 22q11microdeletion syndrome

  29. Patau syndrome • 47,XX(XY), +13 • 1 in 5000-10 000 newborns, • 1 in 90 SA • CLP bilateral, congenitaldefectsofthebrain, eyes, postaxialhexadaktyly…)

  30. Edwards syndrome • 47,XX(XY),+18 • 1in 5000 newborns • IUGR • microcephaly • dolichocephaly • CP • rethrognathia

  31. Wolf-Hirschhorn syndrome, 4p- 1:50 000 8% de novo deletion 13% due to familialtranslocation F:M 2:1 symptoms -dwarfism -microcefaly, craniofacialstigmatisation - CL,CP,CLP -heartdefects

  32. DiGeorge syndrome– velocardiofacial • Microdeletion 22q11 • Symptoms: - heartdefects - facialstigmatisation - CP( submucoustoo) - hypoplasiaofthymusandparathyroids) ( immunodefects, hypocalcemia)

  33. SyndromeswithoutMendelian inheritance • Pierre-Robin sequence • Mandibularhypoplasia • Glossoptosis • Cleftofpalate May be part of a variety of skeletalormuscularsyndromes, somemendelian (e.g. Sticklersy, Congenitalmyotonicdystrophy)

  34. AD hereditarysyndromeswith CLP • van der Woude syndrome • EEC syndrome • Stickler syndrome • Larsen syndrome

  35. van der Woude syndrome -Autosomal dominant, incomplet penetrance variableexpressivity !!! -Mouthlower lip pits-Cleft lip-Cleftpalate-Cleft uvula-Hypodontia • Molecular Basis - caused by mutations in the interferon regulatoryfactor 6 gene (IRF6) -

  36. EEC syndrome -Ectrodaktyly-deformities of hands and feet -Ectodermaldysplasia-skin ,hair,nails -Cleft lip/palate -otherdefects-kidneys,eyes,teeth Genetic heterogenity Two loci described – EEC1(7q11) and EEC3 (3q28) Majority of EEC cases appear to be to TP63 mutations

  37. Incidence 1 in 10 000 Mutation in COL11A1,COL11A2,COL2A1 genes Symptoms -Pierre-Robin sequence -eye:glaucoma,cataracts, retinaldetachment -sensorineuralhearingloss -artropathy, scoliosis,mitralvalve prolaps Stickler syndrome

  38. Larsen syndrome Incidence 1 in 100 000 Caused by mutation in the filamin B gene (FLNB)-3p14.3 Multiple joint dislocation Deformitiesoffeet Facialstigmatisation Others: dwarfism, skeletaldefects , heartdefects, CP, deafness, mentalretardation Rare AR inheritance

  39. AR hereditarysyndromeswith CLP • Fryns syndrome • Roberts syndrome( pseudothalidomid) • Diastrophicdysplasia • Smith-Lemli-Opitz syndrome • Orofaciodigital syndrome II • Meckel-Gruber syndrome

  40. Fryns syndrome • Diaphragmatichernia • Abnormalface,anddistal limb anomalies • Cleft lip/palate

  41. Roberts syndrome • Pseudothalidomid syndrome • Pre-/postnatalgrowthdeficiency • Cleft lip/ palate( bilat.) • cataracta • Oligodactyly • Phocomelia • Radialhypoplasia • Mentalretardation • Caused by mutations in ESCO2 gene (8p21)

  42. Diastrophicdysplasia - dwarfism, adulthigh 100-120 cm -shortlimbs -short, thick tubular bone, with broad metaphyses and flattened, irregular epiphyses -cleftpalate -earabnormalities -joint deformities -hipcontractures -handsdeformities(„ hitchhikerthumb“) -vertebraldeformities SLC26A2 gene (5q32)

  43. Smith-Lemli-Opitz syndrome • pre- andpostnatalgrowthdeficiency • Microcephaly • Facialstigmatisation • Cleftpalate • Mentalretardation • Hypospadias,ambiguousgenitalia,micropenis • Syndaktylyofsecondandthirdtoesoffeet • Mutation in DHCR gene, locus 11q12-q13 • low cholesterol,elevated 7-dehydrocholesterol

  44. Orofaciodigital syndrome, type II • Mohr syndrome • Medialcleftofupper lip • micrognathia • Cleftandlobationoftongue, • hypertelorism • Bilateralpostaxialhexadactylyofhands, bilateralpolysyndaktylyofhallux

  45. Meckel-Gruber syndrome microcephaly, encephalocele Microphtalmia Cleft lip and/orpalate Congenitaldefectofheart Postaxialpolydactyly Polycystickidneys A lethaldisorder, withdeathoccuring in theperinatal period Heterogenity:loc.17q21-24,11q13 and 8q24

  46. X-linkedhereditarysyndromeswith CLP • Orofaciodigital syndrome, type I • Otopalatodigital syndrome • Isolated X-linkedcleftofpalatewithankyloglossia

  47. Orofaciodigial syndrome,type I • Papillon-Léage-Psaume syndrome • Hyperplasiaoffraenulum • Multiply lobulatedtongue • Hypoplasiaoflateralnasalcartilages • Medialpseudocleftofupper lip • Asymetricalcleftofpalate • Variablemalformationofdigits • Moderatementalretardation

  48. Otopalatodigital syndrome • Type I • A characteristikface(prominent supraorbitalarches, joinedeyebrows,antimongoloidpositionofeyeslits, hypertelorism, a broadandflatrootofthe nose) • Cleftpalate • Conductivehearingloss • Mentalretardation • Somaticretardation • Type II - + other multiple skeletalanomalies

  49. Cleft palate and ankyloglossia X-linked inheritance - Cleft of uvula- heterozygot female - Incomplet cleft of palate - Incompetention of palate - ankyloglossia

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